Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UNIPROT:P10415 (Bcl-2)
33,771 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Inherited mutations of the BRCA1 gene predispose to breast, ovarian, and other cancers. The role of the BRCA1 gene in the maintenance of chromosomal integrity is linked to a number of biological properties of its protein product, including transcriptional regulation. In the present study, we have used suppression subtractive hybridisation (SSH) to identify genes induced by BRCA1 by comparing control MCF7 breast carcinoma cells (driver) with MCF7 cells ectopically expressing BRCA1 (tester) and generated a forward subtracted cDNA library. We screened 500 putative positive clones from this library. Two hundred and ten of these clones were positive by differential screening with forward and reverse subtracted probes and the 65 cDNA clones which showed more than fivefold increase were selected for sequencing analysis. We clustered 46 different genes that share high homology with sequences in the GenBank/EMBL databases. Among these, 30 were genes whose function had been previously identified while the remaining 16 clones were genes with unknown functions. Of particular interest, BRCA1 gene induces the expression of genes encoding DNA repair proteins RAD21 and MSH2, ERBB2/HER2 interacting protein ERBIN, meningioma-associated protein MAC30, and a candidate ovarian tumour-suppressor OVCA1. Northern and Western blot analyses confirmed that the expression of these five genes are up-regulated following BRCA1 overexpression in MCF7 and UBR60-bcl2 cells. This is the first study reporting a set of BRCA1-induced genes in breast carcinoma cells by the SSH technique. We suggest that some known genes identified in this study may provide new insights into the tumour-suppressor function of BRCA1.
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PMID:Identification of genes induced by BRCA1 in breast cancer cells. 1247 Jun 55

Mcl-1L (myeloid cell leukemia-1 long) is an antiapoptotic Bcl-2 family protein discovered as an early induction gene during leukemia cell differentiation. Previously, we identified Mcl-1S (short) as a short splicing variant of the Mcl-1 gene with proapoptotic activity. To identify Mcl-1-interacting proteins, we performed yeast two-hybrid screening and found cDNAs encoding tankyrase 1. This protein possesses poly(ADP-ribose) polymerase activity and presumably facilitates the turnover of substrates following ADP-ribosylation. In yeast and mammalian cells, tankyrase 1 interacts with both Mcl-1L and Mcl-1S, but does not bind to other Bcl-2 family proteins tested. Analysis of truncated tankyrase 1 mutants indicated that the first 10 ankyrin repeats are involved in interaction with Mcl-1. In the N terminus of Mcl-1, a stretch of 25 amino acids is sufficient for binding to tankyrase 1. Overexpression of tankyrase 1 antagonizes both Mcl-1L-mediated cell survival and Mcl-1S-induced cell death. Furthermore, coexpression of tankyrase 1 with Mcl-1L or Mcl-1S decreased the levels of Mcl-1 proteins. Although tankyrase 1 down-regulates Mcl-1 protein expression, no ADP-ribosylation of Mcl-1 was detected. In contrast, overexpression of Mcl-1 proteins suppressed the ADP-ribosylation of the telomeric repeat binding factor 1, another tankyrase 1-interacting protein. Thus, interaction of Mcl-1L and Mcl-1S with tankyrase 1 could serve as a unique mechanism to decrease the expression of these Bcl-2 family proteins, thereby leading to the modulation of the apoptosis pathway.
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PMID:Tankyrase 1 interacts with Mcl-1 proteins and inhibits their regulation of apoptosis. 1247 93

Bcl-2/adenovirus E1B 19 kDa interacting protein 2-like, BNIP-2-like (BNIPL) is a recently cloned and characterized apoptosis-associated protein that shares 72% homology with BNIP-2. It is highly expressed in human placenta and lung. A yeast two-hybrid system was used to obtain two BNIPL-interacting proteins, MIF (macrophage migration inhibitory factor) and GFER (growth factor erv1 (Saccharomyces cerevisiae)-like). The interactions were confirmed by glutathione S-transferase pull-down assay in vitro and co-immunoprecipitation assay in vivo. Colony formation assay and cell proliferation test suggest that overexpression of BNIPL could inhibit the growth of BEL-7402 cells. These findings suggest that BNIPL may physically bind to cell proliferation-related proteins, MIF and GFER.
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PMID:The apoptosis-associated protein BNIPL interacts with two cell proliferation-related proteins, MIF and GFER. 1268 88

CD47 is a surface receptor that induces either coactivation or apoptosis in lymphocytes, depending on the ligand(s) bound. Interestingly, the apoptotic pathway is independent of caspase activation and cytochrome c release and is accompanied by early mitochondrial dysfunction with suppression of mitochondrial membrane potential (Deltapsim). Using CD47 as bait in a yeast two-hybrid system, we identified the Bcl-2 homology 3 (BH3)-only protein 19 kDa interacting protein-3 (BNIP3), a pro-apoptotic member of the Bcl-2 family, as a novel partner. Interaction between CD47 and the BH3-only protein was confirmed by immunoprecipitation analysis, and CD47-induced apoptosis was inhibited by attenuating BNIP3 expression with antisense oligonucleotides. Finally, we showed that the C-terminal domain of thrombospondin-1 (TSP-1), but not signal-regulatory protein (SIRPalpha1), is the ligand for CD47 involved in inducing cell death. Immunofluorescence analysis of CD47 and BNIP3 revealed a partial colocalization of both molecules under basal conditions. After T cell stimulation via CD47, BNIP3 translocates to the mitochondria to induce apoptosis. These results show that the BH3-dependent apoptotic pathways, previously shown to be activated by intracellular pro-apoptotic events, can also be turned on by surface receptors. This new pathway results in a fast induction of cell death resembling necrosis, which is likely to play an important role in lymphocyte regulation at inflammatory sites and/or in the vicinity of thrombosis.
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PMID:CD47 and the 19 kDa interacting protein-3 (BNIP3) in T cell apoptosis. 1269 Jan 8

Hypoxic regions within solid tumors are often resistant to chemotherapy and radiation. BNIP3 (Bcl-2/E1B 19 kDa interacting protein) is a proapoptotic member of the Bcl-2 family that is expressed in hypoxic regions of tumors. During hypoxia, BNIP3 expression is increased in many cell types and upon forced overexpression BNIP3 induces cell death. Herein, we have demonstrated that blockage of hypoxia-induced BNIP3 expression using antisense oligonucleotides against BNIP3 or blockage of BNIP3 function through expression of a mutant form of BNIP3 inhibits hypoxia-induced cell death in human embryonic kidney 293 cells. We have also determined that hypoxia-mediated BNIP3 expression is regulated by the transcription factor, hypoxia-inducible factor-1alpha (HIF-1alpha) in human epithelial cell lines. Furthermore, HIF-1alpha directly binds to a consensus HIF-1alpha-responsive element (HRE) in the human BNIP3 promoter that upon mutation of this HRE site eliminates the hypoxic responsiveness of the promoter. Since BNIP3 is expressed in hypoxic regions of tumors but fails to induce cell death, we determined whether growth factors block BNIP3-induced cell death. Treatment of the breast cancer cell line MCF-7 cells with epidermal growth factor (EGF) or insulin-like growth factor effectively protected these cells from BNIP3-induced cell death. Furthermore, inhibiting EGF receptor signaling using antibodies against ErbB2 (Herceptin) resulted in increased hypoxia-induced cell death in MCF-7 cells. Taken together, BNIP3 plays a role in hypoxia-induced cell death in human epithelial cells that could be circumvented by growth factor signaling.
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PMID:BNIP3 plays a role in hypoxic cell death in human epithelial cells that is inhibited by growth factors EGF and IGF. 1287 18

Cortical dysplasia (CD) is a well-recognized cause of intractable epilepsy, especially in children and is characterized histologically by derangements in cortical development and organization. The objective of this study was to expand the current knowledge of altered gene expression in CD as a first step towards in the identification of additional genes operative in the evolution of CD. Surgical specimens were obtained from eight patients (4 males and 4 females; age range 2-38 years; mean 15 years) with a pathologic diagnosis of CD. Nondysplastic temporal neocortex was obtained from a 2-year-old boy with intractable epilepsy and medial temporal lobe ganglioglioma. After total RNA isolation from frozen brain tissues, we carried out gene expression profiling using a cDNA expression array. Differences in gene expressions between CD and the nondysplastic neocortex were confirmed by semi-quantitative conventional reverse transcription-PCR. Three genes (recombination activating gene 1 (RAG1), heat shock 60 kDa protein 1 (HSP-60), and transforming growth factor beta1 (TGF beta1)) were found to be up-regulated more than two-fold in CD, whereas four genes (phosphoinositide-3-kinase regulatory subunit polypeptide 1 [p85 alpha] (PI3K), frizzled homolog 2 [Drosophila], Bcl-2/adenovirus E1B 19 kDa interacting protein (NIP3), and glia maturation factor beta (GMF beta)) were down-regulated to less than 50% of their normal levels. Interestingly, the majority of genes showing altered expression were associated with apoptosis. Our study demonstrates diverse changes in gene expression in CD. However, it remains to be shown which of these are causally related to the evolution of CD.
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PMID:Gene expression profile analyses of cortical dysplasia by cDNA arrays. 1464 2

The p53 binding protein 2 (53BP2) has been initially identified as an interacting protein to p53 and subsequent studies have shown that it also interacts with Bcl-2 and NF-kappaB p65 subunit. We have previously found that the TP53BP2 gene encoding 53BP2 protein is a single copy gene and has been mapped to the long arm of chromosome 1 at q42.1. The subsequent studies revealed that TP53BP2 encodes two proteins, 53BP2 and ASPP2, of 1005 and 1128 amino acids, respectively. ASPP2 contains additional 123 amino acids to the N-terminus of 53BP2. In this study, we have examined the genomic organization of TP53BP2 transcripts and found that it encodes two mRNA species, either with (53BP2) or without exon 3 (ASPP2), by alternative splicing in various cell lines and tissues. Thus, we propose to call these proteins as 53BP2S (short) and 53BP2L (long), respectively.
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PMID:Expression of 53BP2 and ASPP2 proteins from TP53BP2 gene by alternative splicing. 1476 26

The 19 kD interacting protein 3, Nip3/BNIP3, is a pro-apoptotic member of the Bcl-2 family induced during hypoxia via the hypoxia-inducible factor (HIF) 1. BNIP3 has been linked to both apoptotic and necrotic cell death involving mitochondrial permeability transition. Since apoptotic and necrotic mechanisms may occur in brain ischemia, immunohistochemical changes of BNIP3 were studied at 1, 2, 3 and 7 days after transient global brain ischemia (12.5 min) in ventilated normothermic rats. In control brains, BNIP3-like immunoreactivity was moderately strong in neuronal processes or cytoplasm and absent in the nucleus. In the ischemia-vulnerable CA1 neurons, BNIP3-positive granules were seen in the nucleus at 1 and 2 days, and these neurons were damaged at 3 and 7 days. The resistant CA3 neurons showed nuclear BNIP3 labeling by 1 day and then returned to the normal state. BNIP3-positive granules did not overlap with the nucleolus. Constitutively expressed BNIP3 may participate in apoptotic and necrotic processes after brain ischemia. Nuclear location of BNIP3 after brain ischemia indicates a novel role for the regulation of cell survival in neurons or a general disturbance of the nuclear envelope.
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PMID:Nuclear localization of the hypoxia-regulated pro-apoptotic protein BNIP3 after global brain ischemia in the rat hippocampus. 1497 62

Ubiquitin inhibitors act at many levels to enhance apoptosis signaling. For TNF-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis signaling, there are at least five mechanisms by which apoptosis are regulated by the ubiquitin-proteasome pathway. First, proteasome inhibitors can decrease Fas-like inhibitor protein (FLIP) protein levels in tumors, resulting in increased apoptosis signaling due to increased caspase-8 activation. This appears to involve the ubiquitin ligase TNF receptor activation factor-2 (TRAF2) and acts indirectly by causing cell-cycle arrest at a stage where there is high degradation of the FLIP-TRAF2 complex. Second, the regulation of the proapoptotic Bcl-2 family member BAX occurs indirectly. Apoptosis signaling and caspase activation results in a confirmation change in the normally monomeric BAX, which exposes the BH3 domain of BAX, leading to dimerization and resistance to ubiquitin degradation. BAX then translocates into the mitochondria, resulting in the release of proapoptotic mitochondrial factors such as cytochrome c and second mitochondria-derived activator of caspase (SMAC). This results in the activation of caspase-9 and formation of the apoptosome and efficient apoptosis signaling. A third mechanism of the regulation of TRAIL signaling in the ubiquitin-proteasome pathway is mediated by the inhibitor of apoptosis proteins (IAP) E3 ligases. These IAPs can directly bind to caspases but also can act as ubiquitin ligases for caspases, resulting in the degradation of these caspases. IAP binding to caspases can be inhibited by SMAC, which exhibits a caspase-9 homology domain. The fourth mechanism for apoptosis activation by proteasome inhibitors is through the stabilization of the inhibitor of the kappaB (IkappaB)/NF-kappaB complex and prevention of nuclear translocation of the antiapoptosis transcription factor NF-kappaB. During TRAIL-DR4, DR5 signaling, this pathway is activated by interactions of activated Fas-associated death domain with activated receptor-interacting protein (RIP), which in turn activates NF-kappaB-inducing kinase and phosphorylates IkappaB. Therefore, the inhibition of IkappaB degradation blocks this RIP-mediated antiapoptosis signaling event. Last, p53 protein levels, and susceptibility to apoptosis, can be deregulated by the human homolog Hdm2 (Mdm2) E3 ligase. This process is inhibited by p53 phosphorylation and by sequestration of Mdm2 by ARF. Better mechanisms to inhibit the ubiquitin-proteasome pathway targeted at the ubiquitin-proteasome degradation process itself, or more specifically at the E3 ligases known to modulate and downregulate proapoptosis pathways will lead to the enhancement of TRAIL apoptosis signaling and better cancer therapeutic outcomes act through this pathway.
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PMID:Regulation of apoptosis proteins in cancer cells by ubiquitin. 1502 88

The discovery of an agent that selectively kills tumor cells and not normal cells is the dream of every cancer researcher. Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), first discovered in 1995, was heralded as a selective killer of tumor cells, and its potential is still thought to be high. Almost immediately, broad efforts were made to understand its activity at the molecular level. TRAIL has been shown to interact with the cell surface through five distinct receptors, named death receptor (DR) 4, DR5, decoy receptor (Dc)R1, DcR2, and osteoprotegrin. It activates nuclear factor (NF)-kappaB, c-Jun N-terminal kinases, and apoptosis. The apoptotic signals are mediated through Fas-associated death domain protein (FADD)-mediated recruitment of caspase-8 and caspase-3. Additionally, caspase-8 can cleave Bcl-2 homology domain 3 (BH3)-interfering domain death agonist (Bid), and the cleaved Bid then causes the release of mitochondrial cytochrome c, leading to the activation of pro-caspase-9, which can then activate pro-caspase-3. TRAIL-induced apoptosis is negatively regulated by numerous cellular factors including decoy receptors, cellular FADD-like interleukin 1 beta-converting enzyme (FLICE) interacting protein (cFLIP), cellular inhibitor of apoptosis protein (cIAP), X-linked IAP (XIAP), survivin, and NF-kappaB. Second mitochondria-derived activator of caspases (Smac)?direct IAP binding protein with low pI (DIABLO) mediates proapoptotic signals through inaction of IAP. How the TRAIL-induced apoptosis is downregulated by these factors is discussed in detail in this review. Whether TRAIL selectively kills tumor cells without harming normal cells is also discussed.
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PMID:Regulation of TRAIL-induced apoptosis by ectopic expression of antiapoptotic factors. 1511 Jan 90


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